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Conditions involving release of pro-inflammatory cytokines predispose to ARDS

Eisenhut, M.*

European Journal of Anaesthesiology: September 2007 - Volume 24 - Issue 9 - p 813–814
doi: 10.1017/S026502150700049X
Correspondence
Free

*Luton and Dunstable Hospital NHS Foundation Trust Luton Bedfordshire, UK

Correspondence to: Michael Eisenhut, Luton and Dunstable Hospital NHS Foundation Trust, Luton, Bedfordshire, LU4 ODZ, UK. E-mail: michael_eisenhut@yahoo.com; Tel: +0845 1270127; Fax: +1582 497280

Accepted for publication 12 March 2007

First published online 7 June 2007

EDITOR:

Sadis and colleagues [1] investigated risk factors for the development of ARDS in patients receiving multiple transfusions and found that it was not the number of transfusions but thoracic trauma and hypoxia that were associated with the subsequent development of ARDS. Patients who developed ARDS received significantly more fresh frozen plasma. Previous studies showed that septicaemia is an additional predisposing factor for transfusion-related ARDS [2]. Another condition commonly associated with pulmonary oedema during infusion of large amounts of intravenous fluids is diabetic ketoacidosis [3]. All these conditions with their different pathophysiology have in common the release of large amounts of cytokines including tumour necrosis factor (TNF) and interleukin-1 (IL-1). Transfusion of an anti-CD28 monoclonal antibody into human volunteers stimulated T-cells to release large amounts of these two cytokines and led to pulmonary oedema in all subjects of this trial [4]. The mechanism by which these cytokines lead to or predispose to pulmonary oedema has recently been clarified: Alveolar epithelial fluid clearance in pulmonary oedema is dependent on pulmonary epithelial sodium and chloride transport through the apical alveolar epithelial sodium channel and the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel generating the osmotic gradient, which removes water through alveolar aquaporin channels and paracellular pathways from the alveolar air space [5]. TNF is a powerful down-regulator of alveolar epithelial sodium channel expression and was found to induce pulmonary oedema in various animal studies. IL-1 was found to reduce pulmonary alveolar epithelial sodium channel function and expression and sodium uptake in alveolar type II cells. IL-1 can also reduce pulmonary epithelial chloride transport by down-regulation of prostanoid receptors, which leads to a reduction in cyclic adenosine monophosphate (cAMP) and subsequently in cAMP-dependent CFTR function. Pulmonary oedema in meningococcal septicaemia has recently been associated with reduced systemic chloride channel function [6]. The hypoxia found in patients developing ARDS subsequently indicated a reduced fluid clearance associated with a direct cytokine effect preceding the development of ARDS. The association of ARDS with FFP administration may be related to the fact that TNF caused a coagulopathy [7] prompting the administration of FFP. Contributing to the predisposition to ARDS by inflammatory conditions may be the upregulation of P-selectins on vascular endothelial cells, which facilitates the adhesion of neutrophils in the pulmonary circulation and their subsequent migration into the alveolar space. Neutrophil leucocytes are an important source of IL-1 and TNF production.

Future research needs to focus on treatments that can prevent the development of ARDS associated with cytokine-induced reduction of alveolar fluid clearance. The prophylactic application of beta-agonists, which are able to up-regulate alveolar epithelial sodium and chloride transport and were found to reduce lung water in the recent beta agonist lung injury trial, may be able to reduce the risk of this complication.

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References

1. Sadis C, Dubois MJ, Melot C, Lambermont M, Vincent JL. Are multiple blood transfusions really a cause of acute respiratory distress syndrome? Eur J Anaesthesiol 2006; 7: 1-7.
2. Silliman CC. The two-event model of transfusion-related acute lung injury. Crit Care Med 2006; 34: S124-S131.
3. Dixon AN, Jude EB, Banerjee AK, Bain SC. Simultaneous pulmonary and cerebral oedema, and multiple CNS infarctions as complications of diabetic ketoacidosis: a case report. Diabet Med 2006; 23: 571-573.
4. Suntharalingam G, Perry MR, Ward S et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006; 355: 1018-1028.
5. Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 2002; 82: 569-600.
6. Eisenhut M. Changes in ion transport in inflammatory disease. J Inflamm (London) 2006; 3: 5.
7. Esmon CT. Coagulation and inflammation. J Endotoxin Res 2003; 9: 192-198.
© 2007 European Society of Anaesthesiology